MTHFR,GSTP1,ERCC1基因多态性与结直肠癌FOLFOX化疗方案疗效相关性研究

中国临床药理学与治疗学 ›› 2015, Vol. 20 ›› Issue (1): 75-81.

MTHFR,GSTP1,ERCC1基因多态性与结直肠癌FOLFOX化疗方案疗效相关性研究

沈冬亚¹, 谢海棠², 陈尧³, 肖坚⁴, 张伟³, 张雪¹, 周宏灏¹

¹重庆医科大学生命科学研究院,重庆 400016;
²皖南医学院弋矶山医院临床药学部,芜湖 241001,安徽;
³中南大学临床药理研究所,长沙 410078,湖南;
⁴中南大学湘雅医院药剂科,长沙 410078,湖南

收稿日期:2014-03-27 修回日期:2014-05-07 发布日期:2020-07-20
通讯作者: 周宏灏,通信作者,男,中国工程院院士,博士生导师,研究方向:临床药理学与药物基因组学。Tel:0731-84805380 E-mail:hhzhou2003@163.com
作者简介:沈冬亚,男,在读硕士研究生,研究方向:临床药理学与药物基因组学。Tel:0731-84805380 E-mail:sdy19870621@126.com
基金资助:
国家自然科学基金(81302850,81300204,81173134,81300204);中国博士后科学基金(2013M531817,2013M542146);863计划项目(2012AA02A518)

Association of MTHFR, GSTP1, ERCC1 polymorphisms and response to FOLFOX in colorectal cancer patients

SHEN Dong-ya¹, XIE Hai-tang², CHEN Yao³, XIAO Jian⁴, ZHANG Wei³, ZHANG Xue¹, ZHOU Hong-hao¹

¹School of Life Sciences, Chongqing Medical University, Chongqing 400016, China;
²Yijishan Hospital of Wannan Medical College, Wuhu 241001, Anhui, China;
³Institute of Clinical Pharmacology, Central South University, Changsha 410078, Hunan, China;
⁴Departments of Pharmacy, Xiangya Hospital, Central South University, Changsha 410078, Hunan, China

Received:2014-03-27 Revised:2014-05-07 Published:2020-07-20

摘要/Abstract

摘要： 目的: 探讨亚甲基四氢叶酸还原酶(methylenetetrahydrofolate reductase,MTHFR),谷胱甘肽S转移酶P1(glutathione S-transferase pi-1,GSTP1),核苷酸切除修复交叉互补组-1(excision repair cross-complementing group 1,ERCC1)基因多态性与结直肠癌5-氟尿嘧啶/奥沙利铂/亚叶酸钙(FOLFOX)化疗方案疗效的相关性。方法: 150例晚期大肠癌患者抽取静脉血并提取DNA,用荧光定量PCR和高分辨率溶解曲线分型技术(HRM-SNP)等方法检测患者MTHFR、GSTP1、ERCC1基因型。所有患者均经FOLFOX方案治疗,以实体瘤化疗疗效评价标准(RECIST1.1) 评价疗效。运用SPSS 19.0 结合临床资料进行统计分析。结果: ⑴患者性别,年龄,结直肠癌分期(TNM),肿块部位等和FOLFOX化疗疗效均无明显相关性(P>0.05)。⑵GSTP1 Ile105Val Ile/Ile和Ile/Val+Val/Val有效率分别为19.7%、20.5%,两组基因型之间的OR值为 2.876,95%CI(1.288,6.424),P<0.05;MTHFR Ala222 Val Ala/Ala和Ala/Val+Val/Val有效率分别为 11.8%、28.3%,OR值为 2.236,95%CI(1.020,5.017),P<0.05。结论: GSTP1 Ile105Val 、MTHFR Ala222 Val单核苷酸多态性与结直肠癌对FOLFOX方案化疗疗效相关,检测GSTP1 Ile105Val、MTHFR Ala222Val单核苷酸多态性可能成为预测结直肠癌患者接受FOLFOX方案化疗疗效的指标。

关键词: 结直肠癌, MTHFR,GSTP1,ERCC1, 基因多态性, FOLFOX, 化疗疗效

Abstract: AIM: To investigate the relationship between the polymorphisms of MTHFR, GSTP1,ERCC1 and the response to FOLFOX chemotherapy in advanced colorectal cancer. METHODS: A total of 150 patients diagnosed as an advanced colorectal cancer by the pathology were treated with FOLFOX chemotherapy and DNA of peripheral blood-leukocytes was obtained before the treatment, MTHFR,GSTP1,ERCC1 genetype were detected by the HRM-SNP method. RESULTS: (1)The frequencies of MTHFR429 Glu/Glu, Glu/Ala, Ala/Ala were 59.1%, 37.0%, 3.9%; MTHFR 222 Ala/Ala, Ala/Val, Val/Val were 12.6%,47.2%,40.1%;GSTP1-105 Ile/Ile, Ile/Val,Val/Val genetypes were 63.0%,33.1%,3.9%;ERCC1-118AA, AT,TT genetypes were 50.4%, 41.7%,7.9%,respectively.(2)The effective rate of FOLFOX chemotherapy among patients with GSTP1-105 Ile/Ile,Ile/Val+Val/Val genetypes were 19.7%,20.5%,OR=2.876,95%CI(1.288,6.424),P<0.05;MTHFR 222 Ala/Ala, Ala/Val+Val/Val genetypes were 11.8%,28.3%,OR=2.236, 95%CI(1.020,5.017),P<0.05,respectively,which was a significant difference. CONCLUSION: The polymorphisms of MTHFR,GSTP1,ERCC1 correlates with the clinical response to FOLFOX chemotherapy and the genetype detected by the HRM-SNP method may be a predictor of sensitivity to FOLFOX chemotherapy.

Key words: colorectal cancer, MTHFR,GSTP1,ERCC1, gene polymorphism, FOLFOX, response

中图分类号:

R969

沈冬亚, 谢海棠, 陈尧, 肖坚, 张伟, 张雪, 周宏灏. MTHFR,GSTP1,ERCC1基因多态性与结直肠癌FOLFOX化疗方案疗效相关性研究[J]. 中国临床药理学与治疗学, 2015, 20(1): 75-81.

SHEN Dong-ya, XIE Hai-tang, CHEN Yao, XIAO Jian, ZHANG Wei, ZHANG Xue, ZHOU Hong-hao. Association of MTHFR, GSTP1, ERCC1 polymorphisms and response to FOLFOX in colorectal cancer patients[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2015, 20(1): 75-81.

参考文献

[1] Cortejoso L, García MI, García-Alfonso P,et al. Differential toxicity biomarkers for irinotecan- and oxaliplatin containing chemotherapy in colorectal cancer [J].Cancer Chemother Pharmacol, 2013,71(6):1463-1472.
[2] Kelly H, Goldberg RM.Systemic therapy for metastatic colorectal cancer: current options, current evidence[J]. Clin Oncol,2005,23(20):4553-4560.
[3] Raymond E, Faivre S, Woynarowski JM,et al.Oxaliplatin: mechanism of action and antineoplastic activity[J].Semin Oncol,1998,25(2 Suppl 5):4-12.
[4] Iyer L, Ratain MJ.Clinical pharmacology of camptothecins[J].Cancer Chemother Pharmacol,1998,42(Suppl):S31-S43.
[5] Evans WE, Relling MV.Pharmacogenomics: translating functional genomics into rational therapeutics[J]. Science,1999,286: 487-491.
[6] de Gramont A, Figer A, Seymour M,et al.Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer[J]. Clin Oncol,2000,18 (16): 2938-2947.
[7] Oki E, Emi Y, Akagi Y, et al.Phase II trial of alternating mFOLFOX6 and FOLFIRI regimens in the first-line treatment for unresectable or metastatic colorectal cancer (KSCC0701)[J]. Oncology,2013,84(4):233-239.
[8] Eisenhauer EA, Therasse P, Bogaerts J,et al.New response evaluation criteria in solid tumours:Revised RECIST guideline (version 1.1)[J].Eur J Cancer,2009,45(2):228-247.
[9] Kumamoto K, Ishibashi K, Okada N, et al.Polymorphisms of GSTP1, ERCC2 and TS_3'UTR are associated with the clinical outcome of mFOLFOX6 in colorectal cancer patients[J]. Oncol Lett, 2013,6(3):648-654.
[10] Peklak-Scott C, Smitherman PK, Townsend AJ, et al. Role of glutathione S-transferase P1-1 in the cellular detoxification of cisplatin[J]. Mol Cancer Ther,2008,7(10):3247-3255.
[11] Moscow JA, Fairchild CR, Madden MJ, et al.Expression of anionic glutathione-S-transferase and P-glycoprotein genes in human tissues and tumors[J]. Cancer Res,1989, 49(6): 142-148.
[12] Ban N, Takahashi Y, Takayama T, et al.Transfection of glutathione S-transferase (GST)-pi antisense complementary DNA increases the sensitivity of a colon cancer cell line to adriamycin, cisplatin, melphalan and etoposide[J]. Cancer Res,1996, 56(15): 3577-3582.
[13] Watson MA, Stewart RK, Smith GB, et al.Human gluta-thione S-transferase P1 polymorphisms: relationship to lung tissue enzyme activity and population frequency distribution[J]. Carcinogenesis,1998,19(2): 275-280.
[14] Stoehlmacher J, Park DJ, Zhang W, et al. A multivariate analysis of genomic polymorphisms: prediction of clinical outcome to 5-FU/oxaliplatin combination chemotherapy in refractory colorectal cancer[J]. Br J Cancer,2004,91(2): 344-354.
[15] Chen YC, Tzeng CH, Chen PM, et al.Influence of GSTP1 I105V polymorphism on cumulative neuropathy and outcome of FOLFOX4 treatment in Asian patients with colorectal carcinoma[J].Cancer Sci, 2010,101(2): 530-535.
[16] Watson MA, Stewart RK, Smith GB, et al.Human glutathione S-transferase P1 polymorphisms: relationship to lung tissue enzyme activity and population frequency distribution[J].Carcinogenesis, 1998,19(2): 275-280.
[17] Martin LP, Hamilton TC, Schilder RJ.Platinum resistance: the role of DNA repair pathways[J].Clin Cancer Res,2008,14(5):1291-1295.
[18] Shirota Y, Stoehlmacher J, Brabender J, et al.ERCC1 and thymidylatesynthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil chemotherapy[J]. Clin Oncol, 2001,19(23):4298-4304.
[19] Yin M, Yan J, Martinez-Balibrea E,et al.ERCC1 and ERCC2 polymorphisms predict clinical outcomes of oxaliplatin-based chemotherapies in gastric and colorectal cancer: a systemic review and meta-analysis[J].Clin Cancer Res, 2011,17(6):1632-1640.
[20] Rustum YM, Trave F, Zakrzewski SF, et al.Biochemical and pharmacologic basis for potentiation of 5-fluorouracil action by leucovorin[J]. NCI Monogr,1987, 5: 165-170.
[21] Chéradame S, Etienne MC, Formento P, et al.Tumoral-reduced folates and clinical resistance to fluorouracil-based treatment in head and neck cancer patients[J].ClinOncol,1997,15(7):2604-2610.
[22] Rozen R.Molecular genetics of methylenetetrahydrofolate reductase deficiency[J].Inherti Metab Dis, 1996,19(5): 589-594.
[23] Weisberg I, Tran P, Christensen B,et al.A second genetic polymorphism in methylenetetra-hydrofolate reductase (MTHFR) associated with decreased enzyme activity[J]. Mol Genet Metab, 1998,64(3): 169-172.
[24] DeVos L, Chanson A, Liu Z, et al. Associations between single nucleotide polymorphisms in folate uptake and metabolizing genes with blood folates, homocysteine, and DNA uracil concentrations[J].Am J Clin Nut,2008, 88(4): 1149-1158.
[25] Cohen V, Panet-Raymond V, Sabbaghian N, et al.Methylenetetrahydrofolate reductase polymorphism in advanced colorectal cancer: a novel genomic predictor of clinical response to fluoropyrimidine-based chemotherapy[J].Clin Cancer Res,2003,9(5): 1611-1615.
[26] Marcuello E, Altes A,Menoyo A, et al.Methylenetetrahydrofolate reductase gene polymorphis ms:genomic predictors of clinical response to fluoropyrimidine-based chemotherapy[J] ? Cancer Chemother Pharmacol,2006, 57(6): 835-840.
[27] Suh KW, Kim JH, Kim Y, et al, Which gene is a dominant predictor of response during FOLFOX chemotherapy for the treatment of metastatic colorectal cancer, the MTHFR or XRCC1 gene[J] ? Ann Surg Oncol,2006,13(11): 1379-1385.
[28] Ruzzo A, Graziano F, Loupakis F,et al.Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFOX-4 chemotherapy[J].J Clin Oncol,2007,25(10):1247-1254.
[29] Etienne-Grimaldi MC, Milano G, Maindrault-Goebel F,et al.Methylenetetrahydrofolatereductase (MTHFR) gene polymorphisms and FOLFOX response in colorectal cancer patients Marie-Christine[J].Br J Clin Pharmacol, 2010,69(1):58-66.